Abstract Bioactive natural products continue to serve as leads in the search for novel pharmaceutical agents, those containing heterocyclic rings have been especially successful in this context. In this proposal, we outline a variety of new synthetic chemistry that is expected to provide efficient methods for the construction of natural product and natural product-like molecules; these synthetic molecules will be evaluated for their therapeutic potential in a variety of high throughput screens. In Aim 1 we propose to extend our observations of the feasibility of thio acid-azide click chemistry for amide bond formation in imidazole-containing substrates. Specifically, we outline approaches to a suite of pyrrole-containing thio acides which will enable the introduction of the signature pyrrolecarboxamides found in the oroidin alkaloids. A number of instances have been uncovered where the traditional methods for introduction of this fragment have failed. Our plan is to use an in situ base triggered elimination of the thio acid from a thio ester. We also outline the use of a similar strategy for the preparation of trihaloacetamides and t-butoxy urethane (t- BOC). The second aim focuses on application of these new reagents to completion of the total synthesis of three members of the oroidin alkaloids, specifically nagelamide A, nagelamide C and ageliferin. Synthetic access to each of these targets has been compromised by issues associated with introduction of the pyrrolecarboxamides. Efficient syntheses of the advanced intermediates in all three cases have been developed and application of the chemistry developed in Aim 1 will permit the completion of the synthesis of each of these molecules. The final aim outlines an extremely short, second generation synthesis of ageliferin using a urazole as both the source of two nitrogens and as a scaffolding element to facilitate an intramolecular Diels-Alder reaction of a bis vinylimidazole. Strong preliminary data support the generally feasibility of this chemistry which if successful will provide the shortest total synthesis of ageliferin to date.